PDF(Pubmed)
Abstract：
Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne\'s Disease (JD) in ruminants, which is responsible for significant economic loss to the global dairy industry. Mixed strain infection (MSI) refers to the concurrent infection of a susceptible host with genetically distinct strains of a pathogen, whereas within-host changes in an infecting strain leading to genetically distinguishable progeny is called microevolution. The two processes can influence host-pathogen dynamics, disease progression and outcomes, but not much is known about their prevalence and impact on JD. Therefore, we obtained up to 10 MAP isolates each from 14 high-shedding animals and subjected them to whole-genome sequencing. Twelve of the 14 animals examined showed evidence for the presence of MSIs and microevolution, while the genotypes of MAP isolates from the remaining two animals could be attributed solely to microevolution. All MAP isolates that were otherwise isogenic had differences in short sequence repeats (SSRs), of which SSR1 and SSR2 were the most diverse and homoplastic. Variations in SSR1 and SSR2, which are located in ORF1 and ORF2, respectively, affect the genetic reading frame, leading to protein products with altered sequences and computed structures. The ORF1 gene product is predicted to be a MAP surface protein with possible roles in host immune modulation, but nothing could be inferred regarding the function of ORF2. Both genes are conserved in Mycobacterium avium complex members, but SSR1-based modulation of ORF1 reading frames seems to only occur in MAP, which could have potential implications on the infectivity of this pathogen. IMPORTANCE Johne\'s disease (JD) is a major problem in dairy animals, and concerns have been raised regarding the association of Mycobacterium avium subsp. paratuberculosis (MAP) with Crohn\'s disease in humans. MAP is an extremely slow-growing bacterium with low genome evolutionary rates. Certain short sequence repeats (SSR1 and SSR2) in the MAP chromosome are highly variable and evolve at a faster rate than the rest of the chromosome. In the current study, multiple MAP isolates with genetic variations such as single-nucleotide polymorphisms, and more noticeably, diverse SSRs, could simultaneously infect animals. Variations in SSR1 and SSR2 affect the products of the respective genes containing them. Since multiple MAP isolates can infect the same animal and the possibility that the pathogen undergoes further changes within the host due to unstable SSRs, this could provide a compensative mechanism for an otherwise slow-evolving pathogen to increase phenotypic diversity for overcoming host responses.
摘要：
鸟分枝杆菌亚种。副结核病（MAP）引起约翰病（JD）在反刍动物，这对全球乳制品行业造成了巨大的经济损失。混合菌株感染（MSI）是指易感宿主与遗传上不同的病原体菌株同时感染，而感染菌株的宿主内变化导致遗传上可区分的后代被称为微进化。这两个过程可以影响宿主-病原体的动态，疾病进展和结果，但对它们的患病率和对JD的影响知之甚少。因此,我们从14只高脱落动物中获得了多达10株MAP分离株,并对它们进行了全基因组测序.被检查的14只动物中有12只显示出存在MSI和微观进化的证据，而其余两只动物的MAP分离株的基因型可能仅归因于微进化。所有的MAP分离株，否则是等基因的短序列重复（SSRs）的差异，其中SSR1和SSR2是最多样化和同质的。SSR1和SSR2的变化，分别位于ORF1和ORF2中，影响基因阅读框架，导致序列和计算结构改变的蛋白质产物。ORF1基因产物被预测为MAP表面蛋白，可能在宿主免疫调节中起作用。但无法推断ORF2的功能。这两个基因在鸟分枝杆菌复合体成员中都是保守的，但是基于SSR1的ORF1阅读帧调制似乎只发生在MAP中，这可能对这种病原体的传染性有潜在的影响。重要性约翰病(JD)是奶牛的主要问题,并对鸟分枝杆菌亚种的关联提出了担忧。副结核病（MAP）与人类克罗恩病。MAP是一种生长极其缓慢的细菌，基因组进化率低。MAP染色体中的某些短序列重复(SSR1和SSR2)是高度可变的,并且以比染色体的其余部分更快的速率进化。在目前的研究中,具有单核苷酸多态性等遗传变异的多个MAP分离株，更明显的是，不同的SSR，可以同时感染动物。SSR1和SSR2的变异影响含有它们的各个基因的产物。由于多个MAP分离物可以感染同一只动物，并且由于不稳定的SSR，病原体可能在宿主内发生进一步的变化，这可能为原本进化缓慢的病原体提供补偿机制，以增加表型多样性以克服宿主反应。
